Final analysis: A multicenter phase I study of EMD 525797 (DI17E6), a novel humanized monoclonal antibody to human αv integrins, in progressive castrate-resistant prostate cancer with bone metastases after chemotherapy.

Abstract

231 Background: EMD 525797 is a humanized monoclonal IgG2 antibody specifically targeting αv integrins involved in tumor progression. Methods: The safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of EMD 525797 were assessed in metastatic castrate-resistant prostate cancer (mCRPC) patients (pts). 24 pts (43–80 years) were treated with IV infusions of 250, 500, 1000, or 1500 mg EMD 525797 given over 1 h and received 3 doses (weeks 1, 3, and 5) before response assessment at the end of week 6. Pts without progressive disease could receive further doses every 2 weeks. Dose-limiting toxicities (DLTs) were assessed over the first 6 weeks and safety was monitored until 4 weeks after the last administration of EMD 525797. Results: Final analysis showed that 13 of 24 pts had a longer exposure time than expected (≥84 d): 7 pts had exposure times ≥126 d, 3 pts ≥280 d and 1 pt received EMD 525797 for 534 d (Table). All pts experienced adverse events (AEs), and in 11 pts AEs were considered related to EMD 525797. 4 pts had generalized pruritus, erythema, or rash and 3 pts experienced fatigue, mucosal inflammation, or peripheral edema, but no pt had administration site reactions. Changes in clinical lab values were consistent with basic disease. No DLTs occurred. EMD 525797 showed a dose-dependent, nonlinear PK profile in line with a target-mediated drug disposition. Pt 1 and 2 of the 500 mg cohort had a marked decrease in prostate specific antigen. Pt 1 also had primary tumor shrinkage and normalization of lymph node size. These pts had long-term anti-integrin treatment (297 and 534 d, respectively). Both patients showed additional pain relief. Conclusions: EMD 525797 showed clinical activity in mCPRC pts in salvage setting, pain relief, and tumor regression. EMD 525797 is well tolerated without any premedication and did not show clinically relevant dose-related changes in the safety parameters assessed. [Table: see text]